CMAJ • AUG. 3, 2004; 171 (3)251
斗开头的成语
© 2004 Canadian Medical Association or its licensors
Vitamin B 12(cobalamin) deficiency in elderly patients观望不前
Emmanuel Andrès, Noureddine H. Loukili, Esther Noel, Georges Kaltenbach, Maher Ben Abdelgheni, Anne E. Perrin, Marie Noblet-Dick, Frédéric Maloil, Jean-Louis Schlienger, Jean-Frédéric Blicklé
D O I :10.1503/c m a j .1031155
252JAMC • 3 AO ÛT 2004; 171 (3)
Salivary R-protein
Dietary cobalamin bound to animal protein
Salivary glands
Dietary
intake
HCl Pepsin
R-protein from parietal cells
Intrinsic factor
Jejunum
Methyl-cobalamin
Adenosyl-cobalamin
Distal 80 cm of ileum
Cobalamin transported via portal system bound to transcobalamin I, II and III
Ileal mucosal cell
Cubilin栗子的做法大全
Pancreatic protea
Gastric cretion
Cbl –R-protein complexes creted in bile (5–10 µg/d)
Gall bladder
Dietary deficiency
Nitrous oxide*
Achlorhydria
resulting in inability to ver the animal protein from the cobalamin
Lack of IF with total
gastrectomy or pernicious anemia (idiopathic atrophy of gastric mucosa in
association with antibodies to parietal cells and IF)
Exocrine failure leads to cobalamin
malabsorption (inability to degrade Cbl –R-protein complexes)
心愿的作文Genetic disorders involving plasma transport
Rection or dia of the distal 80 cm of the ileum Genetic disorders involving conversion to coenzyme forms
High concentration of bacteria and certain parasites in small intestine can absorb cobalamin
1
2
金龙鱼
3
4
5
6
C h r i s t i n e K e n n e y
lected by the authors. Using the definitions shown in Box 1, we found a prevalence of greater than 4.8% in a large group of patients in hospital between the ages of 65 and 98(data submitted to the 47th Congress of the French Na-tional Society for Internal Medicine in Bordeaux, June 11–13, 1998).
Cobalamin metabolism and function
Cobalamin metabolism is complex and requires many process, any one of which, if not prent, may lead to cobalamin deficiency.4,13–15The caus of cobalamin defi-ciency are shown in Fig.1and listed in Table 1.
Once metabolized, cobalamin is a cofactor and co-enzyme in many biochemical reactions, including DNA synthesis, methionine synthesis from homocysteine and conversion of propionyl into succinyl coenzyme A from methylmalonate, as shown in Fig. 2.
A typical Western diet contributes 3–30 µg of cobalamin per day toward the estimated daily requirement of 2–5 µg that is recommended by the American Society of Geri-atry,16the US Food an
d Drug Administration and the As-sociation Françai de Sécurité Sanitaire des Aliments.Rerves, which are primarily hepatic, are significant (>1.5mg). The 5- to 10-year delay between the ont of in-sufficient intake and the development of clinical illness is a direct result of the hepatic stores and the enterohepatic cy-cle, whereby cobalamin is excreted in bile and then reab-sorbed in the small intestine (e Fig.1).4,13Between 1%and 5% of free cobalamin (and crystalline cobalamin) is absorbed along the entire intestine by passive diffusion,which explains the mechanism underlying oral treatment of deficiencies associated with pernicious anemia and food-cobalamin malabsorption.4,17,18
In a clinical tting, cobalamin absorption is examined (imperfectly) by the Schilling test.4,8 The test is currently performed as follows: patients are given 1000 µg of cyano-cobalamin intramuscularly at day 1 to saturate the intestinal mucosal cells, followed by 1000 µg of free 58Cocyanocobal-amin orally on day 2. Excess cobalamin, which is not ab-sorbed, is excreted, and the patient’s urine is collected for 24 hours (from day 2 to day 3) and the percentage of la-belled cyanocobalamin is determined. Abnormally low lev-els of cobalamin in the collected urine indicate cas of malabsorption or pernicious anemia; normal levels indicate dietary deficiency, food-cobalamin malabsorption or hereditary cobalamin metabolism deficiencies.
Caus of cobalamin deficiency
In elderly patients, cobalamin deficiency is caud pri-marily by food-cobalamin malabsorption and pernicious anemia. Cobalamin deficiency caud by dietary deficiency or malabsorption (Fig. 1, Table 1) is rarer.1,8,11In our stud-ies, in which we followed a total of more than 200 patients with a proven cobalamin deficiency, food-cobalamin mal-CMAJ • AUG. 3, 2004; 171 (3)
253
Table 1: Stages of cobalamin metabolism and corresponding
caus of cobalamin deficiency
13,15
Stage of cobalamin metabolism Cau of cobalamin deficiency Intake solely through food
Strict vegetarianism without vitamin supplementation
Digestion brings into play haptocorrin, gastric cretions (HCl and pepsin), intrinsic factor,pancreatic
and biliary cretions,enterohepatic cycle Gastrectomy; pernicious anemia (Biermer ’s dia);* food-cobalamin malabsorption*Absorption brings into play intrinsic factor and cubilin Ileal rection; malabsorption;pernicious anemia;* Imerslund syndrome †
Transport by transcobalamins
Congenital deficiency in transcobalamin II †
Intracellular metabolism bad on various intracellular enzymes Congenital deficiency in various intracellular enzymes †
Note: HCl = hydrochloric acid.
*Very frequent cau among elderly people.
†Rare cau among adults, even more so among elderly patients.
Fig. 1: Cobalamin metabolism and corresponding caus of deficiency. Caus of cobalamin deficiency are shown in blue.The metabolic pathway starts when (1) dietary cobalamin (Cbl),obtained through animal foods, enters the stomach bound to animal proteins (P). (2) Pepsin an
d hydrochloric acid (HCl) in the stomach ver the animal protein, releasing free cobalamin.Most of the free cobalamin is then bound to R-protein (R),which is relead from the parietal and salivary cells. Intrinsic factor (IF) is also creted in the stomach, but its binding to cobalamin is weak in the prence of gastric and salivary R-protein. (3) In the duodenum, dietary cobalamin bound to R-protein is joined by cobalamin –R-protein complexes that have been creted in the bile. Pancreatic enzymes degrade both biliary and dietary cobalamin –R-protein complexes, releasing free cobalamin. (4) The cobalamin then binds with intrinsic factor. The cobalamin –intrinsic factor complex remains undis-turbed until the distal 80 cm of the ileum, where (5) it attaches to mucosal cell receptors (cubilin) and the cobalamin is bound to transport proteins known as transcobalamin I, II and III (TCI,TCII and TCIII). Transcobalamin II, although it reprents only a small fraction (about 10%) of the transcobalamins, is the most important becau it is able to deliver cobalamin to all cells in the body. The cobalamin is subquently transported systemi-cally via the portal system. (6) Within each cell, the transcobal-amin II –cobalamin complex is taken up by means of endocyto-sis and the cobalamin is liberated and then converted enzymatically into its 2 coenzyme forms, methylcobalamin and adenosylcobalamin (this process is shown in greater detail in Fig. 2).
*Nitrous oxide, a general anesthetic, caus multiple defects in cobalamin u, most of which are int
racellular and clinically relevant only in people who have low or borderline-low rum cobalamin levels.
254
JAMC • 3 AO ÛT 2004; 171 (3)
相形见绌什么意思Methionine S-Adenosyl methionine
Dimethyl-glycine Betaine
S-Adenosyl homocysteine
Homocysteine
5-Methyl 5,10-Methylene tetrahydrofolate
Methyl
tetrahydrofolate
白葡萄酒杯reducta Riboflavin
Tetrahydrofolate
Nucleic acid
synthesis
Methionine syntha Cob(I)alamin
BHMT
Plasma membrane
Cbl III I
TCII
T II C
Reducta
Mitochondria dr
M et Met
Methionine
MeCbl
H 4PteGlu 5-CH H 4PteGlu
Homocysteine
Methionine syntha
oA
absorption accounted for about 60%–70% of the cas among elderly patients, and pernicious anemia accounted for 15%–20% of the cas.14,19,20,21Other caus included di-etary deficiency (< 5%), malabsorption (< 5%) and heredi-tary cobalamin metabolism dias (< 1%).
Food-cobalamin malabsorption
First described by Carmel in 1995,22food-cobalamin mal-absorption syndrome is characterized by the inability to relea cobalamin from food or from intestinal transport pro-teins (Table 1), particularly in the prence of hypo-chlorhydria, where the absorption of “unbound” cobalamin remains normal. As various studies have shown,14,22,23this syn-drome is defined by cobalamin deficiency in the prence of sufficient food-cobalamin intake and a negative Schilling test, where the latter rules out malabsorption or pernicious anemia (Box 2). In theory — becau the test is rarely practical in clinical ttings —the indisputable evidence of food-cobal-amin malabsorption comes from using a modified Schilling test, which us radioactive cobalamin bound to animal pro-teins (e.g., salmon, trout) and reveals malabsorption when the results of a standard Schilling test are normal.4,22
Food-cobalamin malabsorption is caud primarily by gastric atrophy. Over 40% of patients older than 80 years have gastric atrophy that may or may not be related to He-licobacter pylori infection.11,24Other factors that contribute to food-cobalamin malabsorption in elderly people include chronic carriage of H. pylori and intestinal microbial prolif-eration (which can be caud by antibiotic treatment);25 long-term ingestion of biguanides (metformin)26,27and antacids, including H
2
-receptor antagonists and proton pump inhibitors28,29(particularly among patients with Zollinger–Ellison syndrome30);chronic alcoholism; surgery or gastric reconstruction (e.g., bypass surgery for obesity); partial pancreatic exocrine failure;4,14and Sjögren’s syn-drome31(Box 2).
Pernicious anemia
Pernicious anemia, or Biermer’s dia, is a classic cau of cobalamin deficiency and one of the most frequent among elderly patients: 20%–50% of cas according to 2 studies32,33and more than 15% in our patient ries.14,19,20,21 Pernicious anemia is an autoimmune dia characterized by the destruction of the gastric mucosa, especially fundal mucosa, by a primarily cell-mediated process.34Gastric -cretions are neutral to slightly acidic even in the prence of gastrin (which normally increas acidity) and contain little or no intrinsic factor.13,32,34The dia is also charac-terized by the prence of 2 antibodies, particularly in plas-ma and gastric cretions: few people who do not have the dia have antibodies (specificity 98%). However, only about 50% of patients with pernicious anemia will have anti-intrinsic factor antibodies (nsitivity 50%). Anti-gastric parietal cell antibodies, which target the H+/K+adenosine triphosphata alpha and beta subunits, c
an also be measured in the rum; nsitivity is higher (> 90%), but specificity is much lower (50%).32,34Moderate hypergas-trinemia, and sometimes major hypergastrinemia (levels of up to 4 to 8 times above normal), has also been associated with pernicious anemia. Owing to gastric atrophy with hypochlorhydria, patients have a feedback hypergastrine-mia with hyperplasia of antral G cells. Hypergastrinemia is suggestive but not pathognomonic of pernicious anemia (nsitivity > 80%, specificity < 50%).32,33A positive Schilling test (with the addition of a test for anti-intrinsic factor antibodies) virtually confirms the diagnosis (speci-ficity > 99%).21,32
From a clinical perspective, pernicious anemia is asso-ciated with many autoimmune disorders, including vi-tiligo, dysthyroidia, Addison’s dia and Sjögren’s syn-drome.21,32It is also associated with an incread frequency of gastric neoplasms: adenocarcinomas, lymphomas and carcinoid tumours.32,33Most experts recommend that pa-tients with pernicious anemia undergo endoscopic surveil-lance every 3 to 5 years with multiple biopsies, even in the abnce of macroscopic lesions.21This practice has re-cently revealed the near abnce of mucosal H. pylori in patients with the dia.21
CMAJ • AUG. 3, 2004; 171 (3)255 Box 2: Indications of food-cobalamin
malabsorption syndrome*14,19
•Serum cobalamin level < 150 pmol/L
•Result of standard Schilling test (with free
cyanocobalamin marked with cobalt-58) is normal,
or result of modified Schilling test (using radioactive
cobalamin bound to food protein) is abnormal†
•No dietary cobalamin deficiency (intake > 2 µg per
day)
•Existence of a predisposing factor in cobalamin
deficiency:
-Atrophic gastritis, chronic Helicobacter pylori
infection
-
Microbial proliferation, AIDS
-Long-term ingestion of antacids (H
2
-receptor
antagonists or proton pump inhibitors) or
biguanides
-Chronic alcoholism
-Gastrectomy, gastric bypass surgery
-Pancreatic exocrine failure
-Idiopathic (age-related)
*The first 3 items are required for a diagnosis of food-cobalamin
malabsorption.
大洞穴†The modified Schilling test us cobalamin bound to egg, chicken or
fish proteins.4
